This invention relates to certain N-(arylpropyl), N-(aryloxyethyl), and N-(arylallyl)-carboxamides, their agriculturally suitable salts and compositions, and methods of their use as fungicides.
The control of plant diseases caused by fungal plant pathogens is extremely important in achieving high crop efficiency. Plant disease damage to ornamental, vegetable, field, cereal, and fruit crops can cause significant reduction in productivity and thereby result in increased costs to the consumer. Many products are commercially available for these purposes, but the need continues for new compounds which are more effective, less costly, less toxic, environmentally safer or have different modes of action.
U.S. Pat. No. 4,710,518 discloses compounds of Formula i and compositions thereof as fungicides: 
wherein
X is halogen;
n is 1 or 2;
R1 is hydrogen, halogen or lower alkyl;
R2 is lower alkyl, halogen-substituted lower alkyl or hydrogen; and
R3 is hydrogen or lower alkyl.
U.S. Pat. No. 4,946,867 discloses compounds of Formula ii, and compositions and method of use thereof, as fungicides: 
wherein
R is C2-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl or C3-C6 cycloalkyl; and
X is Cl, Br, CF3 or lower fluoroalkoxy group.
This invention is directed to compounds of Formula I (including all geometric and stereoisomers), agricultural compositions containing them and their use as fungicides: 
wherein 
X is xe2x80x94Oxe2x80x94, xe2x80x94CH(R11)xe2x80x94 or xe2x95x90C(R11)xe2x80x94;
R1 is H or C1-C2 alkyl;
R2 is H; C1-C6 alkyl; C3-C6 cycloalkyl; or phenyl optionally substituted with halogen, cyano, C1-C2 alkyl or C1-C2 alkoxy;
R3 is H, C1-C3 alkyl optionally substituted with halogen or CN;
R4 is H or C1-C2 alkyl; or
R3 and R4 can be taken together as xe2x80x94CH2CH2CH2xe2x80x94 or xe2x80x94CH2CH2CH2CH2CH2xe2x80x94;
R5 is H, C1-C2 alkyl optionally substituted with halogen or CN;
R6 is C2-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C2-C8 alkynylalkenyl or C3-C8 cycloalkyl, each optionally substituted with halogen;
R7 is H, CN, halogen, C1-C2 haloalkoxy or C1-C2 haloalkylthio; or C1-C4 alkyl C2-C4 alkenyl or C2-C4 alkynyl, each optionally, substituted with halogen or CN;
R8, R9 and R10 are each independently H, halogen, C1-C3 alkyl, C1-C3 haloalkyl, or Si(CH3)3; and
R11 is H, C1-C5 alkyl, C2-C5 alkenyl or C2-C5 alkynyl.
In the above recitations, the term xe2x80x9calkylxe2x80x9d, used in compound words such as xe2x80x9chaloalkylxe2x80x9d includes straight-chain or branched alkyl, such as, methyl, ethyl, n-propyl or i-propyl. The term xe2x80x9calkylxe2x80x9d, used alone includes straight-chain or branched alkyl, such as, methyl, ethyl, n-propyl, i-propyl, or the different butyl, pentyl, hexyl, heptyl or octyl isomers. xe2x80x9cAlkenylxe2x80x9d includes straight-chain or branched alkenes such as vinyl, 1-propenyl, 2-propenyl and the different butenyl, pentenyl, hexenyl, heptenyl and octenyl isomers. xe2x80x9cAlkenylxe2x80x9d also includes polyenes such as 1,2-propadienyl and 2,4-hexadienyl. xe2x80x9cAlkynylxe2x80x9d includes straight-chain or branched alkynes such as ethynyl, 1-propynyl, 2-propynyl and the different butynyl, pentynyl, hexynyl, heptynyl and octynyl isomers. xe2x80x9cAlkynylxe2x80x9d can also include moieties comprised of multiple triple bonds such as 2,5-hexadiynyl. xe2x80x9cCycloalkylxe2x80x9d includes, for example, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. xe2x80x9cAlkynylalkenylxe2x80x9d is a compound word and includes straight-chain or branched alkyne substituted on a straight-chain or branched alkene. Examples ofxe2x80x9calkynylalkenylxe2x80x9d include H2Cxe2x95x90CHC(CH3)(Cxe2x89xa1CH) and HCxe2x89xa1CCHxe2x95x90CHC(CH3)2.
In the above recitations, the term xe2x80x9calkoxyxe2x80x9d, used in compound words such as xe2x80x9chaloalkoxyxe2x80x9d or xe2x80x9chaloalkylthioxe2x80x9d includes methyl and ethyl. Examples ofxe2x80x9chaloalkoxyxe2x80x9d include CF3CH2O, CF3O, CHF2CF2O, HF2CO and CCl3CCl2O. Examples of xe2x80x9chaloalkyl xe2x80x9d include CF3S, HF2CS, CCl3S, CHF2CF2S and CF3CH2S.
The term xe2x80x9chalogenxe2x80x9d, either alone, when a group is xe2x80x9coptionally substituted with halogenxe2x80x9d or in compound words such as xe2x80x9chaloalkylxe2x80x9d, xe2x80x9chaloalkoxyxe2x80x9d or xe2x80x9chaloalkylthioxe2x80x9d; includes fluorine, chlorine, bromine or iodine. Further, when used in compound words such as xe2x80x9chaloalkylxe2x80x9d or when a group is xe2x80x9coptionally substituted with halogenxe2x80x9d, said alkyl or group may be partially or fully substituted with halogen atoms which may be the same or different. Examples of xe2x80x9chaloalkylxe2x80x9d include F3C, ClCH2, CF3CH2 and CF3CCl2. Examples of an alkyl group xe2x80x9coptionally substituted with halogenxe2x80x9d include CH(F)xe2x95x90CHC(CH3)(CH2F) and CH2xe2x95x90CHC(CH3)(CH2F).
The total number of carbon atoms in a substituent group is indicated by the xe2x80x9cCi-Cjxe2x80x9d prefix where i and j are numbers from 1 to 6. For example, C1-C3 alkyl designates methyl through propyl. When a group contains a substituent which can be hydrogen, for example R1 or R3, then, when this substituent is taken as hydrogen, it is recognized that this is equivalent to said group being unsubstituted.
Compounds of this invention can exist as one or more stereoisomers. The various stereoisomers include enantiomers, diastereomers, atropisomers and geometric isomers. One skilled in the art will appreciate that one stereoisomer may be more active and/or may exhibit beneficial effects when enriched relative to the other stereoisomer(s) or when separated from the other stereoisomer(s). Additionally, the skilled artisan knows how to separate, enrich, and/or to selectively prepare said stereoisomers. Accordingly, the present invention comprises compounds selected from Formula I. The compounds of the invention may be present as a mixture of stereoisomers, individual stereoisomers, or as an optically active form.
Of note are compounds where R7 is other than H, especially when Z is Z-1. Also of note are compounds where R7 is hydrogen and R8 is other than hydrogen and when Z is Z-1 is attached to the carbon adjacent to the R7 substituted carbon. Further of note are compounds where the carbon attached to R1 has the (R) configuration.
Also of note are compounds wherein R1 is H or CH3; R2 is H or CH3; R6 is C2-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl or C3-C6 cycloalkyl each optionally substituted with halogen; and R7 is H, CN, halogen, C1-C4 haloalkyl, C1-C4 alkyl, C2-C4 alkenyl or C2-C4 alkynyl each optionally substituted with halogen or CN.
Compounds of the invention include compounds of Formula Ia, Ib and Ic. 
Preferred compounds for reasons of better activity and/or ease of synthesis are:
Preferred 1. Compounds of Formula I above and agriculturally suitable salts thereof, wherein:
Q is Q-1;
R1 is CH3;
R2 is H;
R3 is CH2CH3; and
R4 is CH3.
Preferred 2. Compounds of Preferred 1 wherein:
Z is Z-1 or Z-4;
R7 is H, halogen, CN, C1-C4 alkyl or C2-C4 alkenyl;
R8 is H or F and is in the para position with respect to X when Z is Z-1; and
R9 is in the para position with respect to R7 when Z is Z-1.
Preferred 3. Compounds of Preferred 1 wherein:
Z is Z-2 or Z-3; and
R7 is H, halogen; CN, C1-C3 alkyl or C2-C4 alkenyl.
Preferred 4. Compounds of Formula I above and agriculturally suitable salts thereof, wherein:
Q is Q-2;
R1 is CH3;
R2 is H or phenyl optionally substituted with halogen, cyano, C1-C2 alkyl or C1-C2 alkoxy; and
R6 is C2-C6 alkyl or C2-C6 alkenyl each optionally substituted with halogen.
Preferred 5. Compounds of Preferred 4 wherein:
Z is Z-1 or Z-4;
R7 is H, halogen, C1-C3 alkyl, C2-C4 alkenyl or C2-C4 alkynyl;
R8 is H or F and is in the para position with respect to X when Z is Z-1; and
R9 is in the para position with respect to R7 when Z is Z-1.
Preferred 6. Compounds of Preferred 4 wherein:
Z is Z-2 or Z-3; and
R7 is H, halogen, C1-C4 alkyl, C2-C4 alkenyl or C2-C4 alkynyl.
This invention also relates to fungicidal compositions comprising fungicidally effective amounts of the compounds of the invention and at least one of a surfactant, a solid diluent or a liquid diluent. The preferred compositions of the present invention are those which comprise the above preferred compounds.
This invention also relates to a method for controlling plant diseases caused by fungal plant pathogens comprising applying to the plant or portion thereof, or to the plant seed or seedling, a fungicidally effective amount of the compounds of the invention (e.g., as a composition described herein). The preferred methods of use are those involving the above preferred compounds.
The compounds of Formula I can be prepared by one or more of the following methods and variations as described in Schemes 1. The definitions of Q, R1, R2, R3, R4, R5, R6, R7, R8.
R9, R10, R11. X and Z in the compounds of Formulae I-XXXIII below are as defined above in the Summary of the Invention. 
When A is OH, the amine of Formula II is condensed with the carboxylic acid of Formula III in the presence of a dehydrating reagent, such as N,Nxe2x80x2-dicyclohexylcarbodiimide (DCC) or carbonyl diimidazole (CDI), in the presence of an inert solvent. The process can be carried out over a wide temperature range in a wide variety of solvents. Generally, the condensation is carried out at a temperature between 20xc2x0 C. and the boiling point of the reaction mixture, preferably about 100xc2x0 C., for 0.1 to 72 h. Examples of suitable solvents include methylene chloride, toluene, diethyl ether, tetrahydrofuran, acetone and acetonitrile.
When A is chlorine, the amine of Formula II is condensed with the carboxylic acid chloride of Formula III in the presence of an acid acceptor such as triethylamine, in an inert solvent. Suitable reaction temperatures, times, solvents, and pressures are the same as described for the condensation wherein A is OH.
The amines of Formula II are known or can be prepared by a variety of methods. Formula II amines can be prepared from carbamates IV wherein R12 is typically t-butyl or benzyl or from V in which Y is typically phenyl (forming a phthalimide ring) or bis-t-butoxycarbonyl (forming a bis-t-butoxycarbonyl protecting group). The removal of the carbamate and phthalimide protecting groups of IV and V to form II can be effected by methods set out in the literature such as those referenced in Greene, T. W. Protective Groups in Organic Synthesis; John Wiley and Sons, New York, N.Y., (1991), Chapter 7. 
The compounds of Formulas IVa and Va in which X is carbon with a double bond attachment are subsets of Formula IV and V compounds and can be prepared by treatment of protected amines of Formulas VIa and VIb, respectively, with aromatic bromides or iodides (for the cases in which Z is phenyl or thiophene) of Formula VII and 1-10 mole % of an appropriate Pd (II) catalyst. Appropriate catalysts include PdCl2 and Pd(OAc)2 complexed with a 2-4 fold excess of a phosphine ligand such as triphenylphosphine. The reactions are performed between 0xc2x0 C. and 100xc2x0 C. with a 1-3 molar equivalents of a base such as K2CO3 or triethylamine. Oftentimes 10-50 mole % of an ammonium phase transfer catalyst is used in the reaction mixture. Typical solvents include acetonitrile or dimethylformamide. 
Formula VI compounds are made from the corresponding unprotected amines by methods set out in the literature such as those referenced in Greene, T. W., Protective Groups in Organic Synthesis; John Wiley and Sons, New York, N.Y., (1991), Chapter 7. Alternatively, they may be prepared by displacement of a leaving group LG from compounds of Formula VIII with carbamates or diimides of Formula IXa or IXb in the presence of a base such as alkoxide salts as potassium t-butoxide, hydride salts as sodium hydride, or amine bases as diisopropyl ethylamine. Typical leaving groups LG includes chloride, bromide, iodide, (methylsulfonyl)oxy or [(4-methylphenyl)sulfonyl]oxy. 
Formula VII, VIII and IX compounds are commercially available or are synthesized by procedures set out in the literature.
Alternatively, compounds of Formula IVa (for the cases in which Z is phenyl or thiophene) can be made from compounds of Formula XXXV by treatment with a phosphine such as triphenylphosphine in the presence of aromatic aldehydes and ketones of Formula XXXVI. The reactions are run in ethereal solvents such as glyme or tetrahydrofuran, hydrocarbon solvents such as toluene or protic solvents such as isopropyl alcohol or ethanol at temperatures ranging between 20xc2x0 C. and 150xc2x0 C. Formula XXXV and XXXVI are either commercially available or easily synthesized by methods set out in the literature. 
Compounds of Formulas IVb and Vb are a subset of Formula IV and Formula V compounds in which X is carbon with a single bond attachment and can be prepared from compounds of Formulas IVa and Va, respectively, by hydrogenation over an appropriate transition metal catalyst such as palladium, platinum or rhodium. Typically the catalyst is deposited over an inert support such as carbon, alumina or calcium carbonate. The hydrogenations are carried out in protic solvents such as ethanol or non-protic solvents such as tetrahydrofuran or ethyl acetate. Pressures of 1-10 torr of hydrogen are required. The hydrogenations are run at 25xc2x0 C. but may be run at temperatures up to 100xc2x0 C. 
Alternatively, compounds of Formula IIb in which Z is phenyl or thiophene and X is carbon with a single bond attachment can be prepared from compounds of Formula X by reductive amination with an excess of an ammonium halide or acetate salt in the presence of a 1-10 equivalents of hydride reducing reagent such as sodium or tetrabutyl cyanoborohydride or sodium triacetoxyborohydride. The reaction can be run in protic solvents such as methanol or in aprotic solvents such as tetrahydrofuran or dichloromethane. An acid catalyst such as HCl or p-toluenesulfonic acid is often added portionwise so as to maintain a pH of 3-5 as determined by a pH meter or an indicator dye such as bromocresol green or methyl orange. Typical temperatures for the reductive aminations range from xe2x88x925xc2x0 C. to 60xc2x0 C. 
Compounds of Formula X can be prepared from compounds of Formula XI in which Z is phenyl or thiophene by hydrogenation under the conditions described for the conversion of compounds IVa and Va to compounds IVb and Vb. Compounds of Formula XI can be prepared by olefination of compounds of Formula XII in which Z is phenyl or thiophene with an appropriate triphenylphosphonium ylide or an appropriate phophonate anion. The olefination reactions are typically carried out in ethereal solvents such as tetrahydrofuran or dimethoxyethane or in polar aprotic solvents such as dimethylsulfoxide or dimethylformamide at temperatures ranging from 0 to the 100xc2x0 C. The ylides and phosphonate anions are generated with alkoxide or hydride bases respectively and by methods set out otherwise in the literature (see March J. Advanced Organic Chemistry; John Wiley and Sons: New York, (1992); 4th Ed., pp 956-963). 
Compounds of Formula IVb or Vb in which Z is pyrrolyl can be prepared by displacement of the leaving group LG of compounds of Formulas XIIIa or XIIIb in the presence of an acid acceptor which can be a tertiary amine such as triethylamine, an alkoxide such as potassium t-butoxide or a carbonate such as potassium carbonate. The leaving group LG is as described for Formula VIII compounds. The displacements can be carried out in polar aprotic solvents such as dimethylformamnide or dimethylsulfoxide, ethereal solvents such as tetrahydrofuran or dioxane, or in protic solvents such as ethanol. Reaction temperatures can vary from 20xc2x0 C. to 150xc2x0 C. 
Compounds of Formula XIII can be prepared from the compounds of Formulas XIVa or XIVb by standard methods for the conversion of alcohols to halides (March, J. Advanced Organic Chemistry; John Wiley and Sons: New York, (1992); 4th Ed., pp 431-433) and for the conversion of alcohols to sulfonates (March, J. Advanced Organic Chemistry; John Wiley and Sons: New York, (1992); 4th Ed., pp 498-499). Compounds XIV can, in turn, be prepared from the aminoalcohol by methods set out in the literature such as those referenced in Greene, T. W. Protective Groups in Organic Synthesis; John Wiley and Sons, New York, N.Y., (1991), Chapter 7. 
Compounds of Formula IVc and Vc are a subset of compounds of Formula IV in which X is O and can be prepared from compounds of Formula XVa and XVb, respectively, by displacement of the leaving group LG with compounds of Formula XVI under conditions as described for the conversion of XIII to IVb and Vb. The leaving group LG is as described for Formula VIII compounds. Formula XVa and XVb compounds can be prepared from the corresponding alcohols XVIIa and XVIIb as described for Formula XIII compounds. Alternatively, IVc and Vc can be prepared directly from XVIIa and XVIIb, respectively, and XVI in the presence of 1-2 equivalents of triphenylphosphine and 1-2 equivalents of diethylazodicarboxylate. The reaction is generally run in an inert solvent such as methylene chloride or tetrahydrofuran at a temperature range of 0xc2x0 C. to 100xc2x0 C. Compounds of Formula XVI are generally commercially available or can be prepared by methods set out in the literature. For a review of literature methods for when Z is pyrrolyl, see Achesson, R. M. Adv. Heterocycl. Chem. (1990), 51, 115-119. Compounds of Formula XVII are prepared from the corresponding aminoalcohol as described for the preparation of compounds of Formula XIV. 
Alternatively, compounds of Formula IVc in which Z is phenyl or thiophene can be prepared by reaction of compounds XVIIa with base and an activated aryl fluoride of Formula XVIII. Appropriate bases include hydride salts such as sodium hydride, amine salts such as lithium diisopropylamine and alkoxide salts such as potassium t-butoxide. Solvents for the reaction can include ethereal solvents such as tetrahydrofuran or polar aprotic solvents such as dimethylformamide. Reaction temperatures can vary from xe2x88x9220xc2x0 C. to 150xc2x0 C. The reaction is facilitated for the cases in XVIII wherein at least one of R7, R8, R9, or R10 is an electron withdrawing group such as CN or halogen. 
Compounds of Formula IIIa, a subset of Formula II compounds wherein A is OH, can be prepared from the corresponding esters of Formula XIX wherein R13 is C1-C5 alkyl or optionally substituted benzyl via standard methods for ester hydrolysis (see Greene, T. W. Protective Groups in Organic Synthesis; John Wiley and Sons, New York, N.Y., (1991), pp 227-260). 
Compounds of Formula XIXa, a subset of Formula XIX compounds, can be prepared from compounds of Formula XX by treatment with excess dichlorocarbene. Dichlorocarbene can be generated in chloroform solvent and reacted with XX in a biphasic mixture with 5-20 equivalents of sodium or potassium hydroxide facilitated by 1-20 mole % of a tetraalkyl ammonium halide or a crown ether phase transfer catalyst. The reaction is run at temperatures ranging from 0xc2x0 C. to 60xc2x0 C. The conversion of XX to XIXa can also be effected by treatment with 1-5 equivalents of the alkali metal salts of trichloroacetic acid in ethereal solvents such as diglyme or dioxane or aromatic hydrocarbon solvents such as benzene or toluene or under neat conditions. The reaction temperatures can vary from 60xc2x0 C. to 150xc2x0 C. Addition of 1-20 mole % of a phase transfer catalyst such as 18-crown-6 or tetrabutyl ammonium chloride can enhance the reaction. Alternatively, the conversion of XX to XIX can be effected by treatment with 1-5 equivalents of methyl or ethyl esters of trichloroacetic acid in the presence of 1-5 equivalents of sodium methoxide or sodium ethoxide. Appropriate solvents include hydrocarbons such as pentane or cyclohexane, ethers such as tetrahydrofuran or dimethoxyethane or aromatic hydrocarbons such as benzene or toluene. The temperature of the reaction can vary from xe2x88x9220xc2x0 C. to 120xc2x0 C. 
Compounds of Formula XX are prepared via condensation of compounds of Formula XXI and XXII. The conditions for such condensations are described in the references contained in March, J. Advanced Organic Chemistry; John Wiley Sons: New York, (1992,; 4th Ed., pp 944-945. 
Alternatively, compounds of Formula IIIb, a subset of Formula IIIa compounds, can be prepared by oxidation of compounds of Formula XXIII via a variety of methods set out in the literature for the oxidation of alcohols to acids (see Larock, R. C. Comprehensive Organic Transformations; VCH Publishers: New York, (1989), pp 834-837). The dichlorocyclopropane of XXIII can be introduced by reaction of compounds of Formula XXIV via conditions described for the conversion of XX to XIXa. 
The conversion of XXIV to XXIII can sometimes be more efficiently mediated by the use of protecting group chemistry. Thus the alcohol of XXIV can be converted to an ether XXV in which PG can be an alkyl, benzyl or silyl protecting group. Conversion to XXIII is effected by subsequent cyclopropanation to XXVI via conditions described for the conversion of XIX to III followed by removal of the protecting group. Appropriate protecting groups PG and the condition for their introduction and removal are described in Greene, T. W. Protective Groups in Organic Synthesis; John Wiley and Sons, New York, N.Y., (1991), pp 10-86. 
Compounds of Formula XXIV can be prepared from compounds of Formula XXVII by addition of 2-5 equivalents of Grignard reagents XXVIII and quenching via the dropwise addition of an excess of either a protic solvent such as water, methanol or acetic acid optionally containing a dissolved proton donor such as ammonium chloride or hydrogen chloride or a reagent of Formula XXIX in which LG is a leaving group as described for Formula VIII compounds. The reaction is performed in ethereal solvents such as diethyl ether or tetrahydrofuran at temperatures ranging from 0xc2x0 C. to 60xc2x0 C. with quenching carried out at temperatures ranging from xe2x88x9220xc2x0 C. to 30xc2x0 C. 
Alternatively, compounds of Formula XXIV can be prepared from compounds of Formula XXX by treatment with a 2-5 equivalents of a Grignard or zinc organometallic reagent of Formula XXXI (M is a magnesium halide or a zinc halide) in the presence of 1-10% of a transition metal catalyst such as ((C6H5)3P)2NiCl2 or ((C6H5)3P)4Pd. The reaction is typically run in an ethereal solvent such as ethyl ether or tetrahydrofuran or a polar aprotic solvent such as dimethylformamide at temperatures ranging from xe2x88x9220xc2x0 C. to 60xc2x0 C. 
Compounds of Formula XXX can be prepared as described for the preparation of compounds of Formula XXIV with the modification that the reaction mixture is quenched with an excess of either I2 or Br2 added dropwise in the chosen reaction solvent. 
Compounds of Formula XIXb, as subset of Formula XIX compounds, are well known in the literature (see, for example, Alexander, E. R.; McCollum, J. D. and Pour, D. E. J. Org. Chem. (1950), 72, 4791-4972; Stevens, R. V.; Christenson, C. G.; Edmonson, W. L.; Kaplan, M.; Reid. E. B.; Wentlant, M. P. J. Am. Chest. Soc. (1971), 93, 6624-6637; and Anonymous, USA Res. Discl. (1985), 55, 249) and can be prepared by addition of a 1-2 equivalents of an alkyl magnesium, copper, zinc or lithium reagent of Formula XXXII in which R16 is C1-C4 alkyl, C2-C4 alkenyl or C2-C4 alkynyl optionally substituted with CN to compounds of Formula XXXIII. R14 and R15 in XXXIII are independently H, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl or C3-C6 cycloalkyl each optionally substituted with halogen. The reaction is typically run in an ethereal solvent such as diethyl ether or tetrahydrofuran at temperatures ranging from xe2x88x9220xc2x0 C. to 60xc2x0 C. Optionally, a Cu (I) catalyst (1-10 mole %) such as copper (I) halide can be added to facilitate the reaction. Alternatively, XXXIII can be hydrogenated to XIXb under the conditions described for the conversion of IVa and Va to IVb and Vb. Compounds of Formula XXXIII are well known in the literature and are prepared by Knoevenagle condensation of cyanoacetic esters with aldehydes and ketones (see Jones, G. Organic Reactions John Wiley and Sons: New York, (1967); Vol. 15 pp 238-244). 
Compounds of Formula IIIc, a subset of Formula IIIa compounds in which Q is Q-2; R14 and R15 are as described previously; and R17; R18, R19 are independently halogen, C1-C2 alkyl, C2 alkenyl, C2 alkynyl each optionally substituted with halogen can be prepared from compounds of Formula XXXIV. The rearrangement of Formula XXXIV compounds to Formula IIIc compounds can be carried out by procedures set out in the literature (see March, J. Advanced Organic Chemistry; John Wiley and Sons: New York, (1992); 4th Ed., pp 1136-1141). Typically XXXXIV is treated with 1 equivalent of a lithium or potassium amide or alkoxide base such as lithium diisopropyl amine or potassium t-butoxide in an inert solvent such as tetrahydrofuran or toluene at temperatures ranging from xe2x88x9278xc2x0 C. to 150xc2x0 C. Additionally, the intermediacy of silyl ketene acetals can be involved for the conversion by heating XXXIV to reflux in a solvent such as hexamethyldisilazane or in an inert solvent such as benzene or toluene in the presence of 1-10 equivalents of hexamethyldisilazane. The product of the silyl ketene acetal mediated rearrangement is a silyl ester which can be converted to the acid by acid or base hydrolysis. 
Compounds of Formula XXXIV can be prepared from compounds of Formula XXXV by standard conditions of esterification (see March, J. Advanced Organic Chemistry; John Wiley and Sons: New York, (1992); 4th Ed., pp 392-401). Formula XXXV compounds are generally commercially available or readily synthesized by methods set out in the literature. 
It is recognized that some reagents and reaction conditions described above for preparing compounds of Formula I may not be compatible with certain functionalities present in the intermediates. In these instances, the incorporation of protection/deprotection sequences or functional group interconversions into the synthesis will aid in obtaining the desired products. The use and choice of the protecting groups will be apparent to one skilled in chemical synthesis (see, for example, Greene, T. W.; Wuts, P. G. M. Protective Groups in Organic Synthesis, 2nd ed.; Wiley: New York, 1991). One skilled in the art will recognize that, in some cases, after the introduction of a given reagent as it is depicted in any individual scheme, it may be necessary to perform additional routine synthetic steps not described in detail to complete the synthesis of compounds of Formula I. One skilled in the art will also recognize that it may be necessary to perform a combination of the steps illustrated in the above schemes in an order other than that implied by the particular sequence presented to prepare the compounds of Formula I.
One skilled in the art will also recognize that compounds of Formula I and the intermediates described herein can be subjected to various electrophilic, nucleophilic, radical, organometallic, oxidation, and reduction reactions to add substituents or modify existing substituents.